SCID-Xl is a catastrophic disease of childhood caused by mutations in the common gamma chain (YC) leading to defects in cytokine signaling that result in profound deficiencies in both cellular and humoral immunity. Patients that have a matched sibling donor for allogeneic transplant do very well with a greater than 90% long-term disease free survival. However, most patients do not have a matched sibling donor available and typically are treated using a haploidentical, parental transplant. These patients do significantly less well with a long term survival ranging between 60 and 75%. Furthermore, persistent immune defects are present in about 50 to 60 % of the survivors of haploidentical transplants. For these children who lack a matched sibling donor, gene therapy is being developed as an alternate primary therapy and as salvage for allogeneic transplant failures. Prior trials in France, the UK, and in the US have used retroviral vectors developed from the Moloney Leukemia Virus (MLV) in which the y{c} cDNA was driven from the strong viral enhancer/promoter present in the long terminal repeat (LTR). These trials have yielded clear proof of efficacy by showing that the majority of patients had significant immune reconstitution following the gene transfer procedure. However, 5 out of 23 patients have developed T cell leukemia due to transcriptional activation of cellular proto-oncogenes from the strong viral enhancer present in the MLV LTR. We now seek to avoid this complication by using a self-inactivating (SIN) lentiviral vector which contains an internal cellular promoter and chromatin insulator fragments flanking the transcriptional cassette. We have tested this CL20i4-EF1a-hy{c}-OPT vector in preclinical experiments that have confirmed the potential safety and efficacy of this configuration. We have also created a high titer, stable producer cell line for GMP production and have generated a Master Cell Bank in our GMP facility. We now propose two clinical protocols to study the use of this vector in either newly diagnosed patients less than one year old (LVXSCID-ND) or in older children that have failed previous treatment or who present later in life with milder symptoms (LVXSCID-OC). We hypothesize that this lentiviral vector-based approach will provide effective treatment and will be safer than the previous MLV-based vectors. These companion clinical trials should yield a great deal of information about gene therapy for SCID-X1 and more generally about the use of lentiviral vectors for stem cell-targeted, human gene therapy.